The ammonolysis of esters in liquid ammonia

The rates of ammonolysis of alkyl benzoate and phenylacetate esters in liquid ammonia increase with the acidity of the leaving group alcohol and show relatively large Brønsted βlg values of −1.18 and −1.34, respectively, when plotted against the aqueous pKa of the alcohol. The Brønsted βlg obtained using the pKa of the leaving group alcohol in liquid ammonia is significantly reduced to ~ −0.7, which indicates that the rate-limiting step involves a reaction of the tetrahedral intermediate with little C–OR bond fission in the transition state. The solvolysis reaction is subject to significant catalysis by ammonium ion, which, surprisingly, generates a similar Brønsted βlg indicating little interaction between the ammonium ion and the leaving group. It is concluded that the rate-limiting step for the ammonium-ion-catalysed solvolysis of alkyl esters in liquid ammonia is the diffusion-controlled protonation of the zwitterionic tetrahedral intermediate T+- to give T+, which is rapidly deprotonated to give T0 which is compatible with the rate-limiting step for the uncatalysed reaction being the formation of the neutral T0 by a ‘proton switc

Mechanism and Catalysis in the Hydrolysis of Some Acetals and Esters

Recent advances in the study of acetal hydrolysis and the effect of neighbouring hydroxyl groups on ester hydrolysis are reviewed. Some of the criteria used to elucidate the mechanism of such reactions are discussed. The enhanced rates of intra-molecular reactions over their inter-molecular counterparts are suggested to be due to factors other than just a 'concentration' effect, product stability reflected in the transition state may be important. Intra-molecular and inter-molecular general-acid catalysis have been detected in the hydrolysis of benzyli-dene 2,3-dioxy benzoic acid and benzylidene catechol, respectively. Several kinetic parameters of these reactions have been determined and are discussed. An example of nucleophilic catalysis by a carboxyl group has been found in the hydrolysis of o-carboxy benzylidene catechol. o-carboxy benzylidene 2,3-dioxy benzoic acid, a system which apparently contains suitably disposed carboxyl groups to act as general-acid and nucleophilic catalysts, was synthesised. However, the hydrolysis of this acetal showed no evidence of bifunctional catalysis. Ring opening during the acid catalysed hydrolysis of benzaldehyde acetals of 2,3-exo-norbornanediol is shown to be reversible. An A-2 mechanism is suggested to be the pathway of hydrolysis of these 1,3-dioxolanes. The facilitated rate of hydrolysis of beta-hydroxy esters, in particular beta-hydroxy butyrates and 2-hydroxy cyclopentane carboxylates, has been shown not to be due to any direct interaction between the two functional groups. 'Solvent sorting' is tentatively suggested to account for the observed phenomenon

Peptide Biomarkers for Identifying the Species Origin of Gelatin Using Coupled UPLC-MS/MS

Liquid chromatography linked with mass spectrometry (LC–MS/MS) was used to analyse gelatin from four different species after a trypsin digest. Using chemometric software to analyse the data it was possible to find peptide fragments that were specific to each species of gelatin: porcine, bovine, chicken or fish. Identification of these peptides was challenging due to the destructive nature of gelatin manufacture. The untargeted workflow method developed allowed identification of 21 unknown gelatin samples with 100% accuracy. Fish gelatin is made from a large range of different species that do not share a common differentiating protein but it was shown that the protein from a parasitic bacteria could be used to identify fish gelatin.</p

Imide and isatin derivatives as β-lactam mimics of β-lactam antibiotics

Activated γ-lactams, which are derivatives of succinimide, phthalimide and isatin with suitable elements of molecular recognition, have been synthesised as mimics of the ß-lactam antibiotics and their chemical and biological reactivity determined

Phosphorothioate Anti-sense Oligonucleotides: The Kinetics and Mechanism of the Generation of the Sulfurising Agent from Phenylacetyl Disulfide (PADS)

The synthesis of phosphorothioate oligonucleotides is often accomplished in the pharmaceutical industry by the sulfurisation of the nucleotide-phosphite using phenylacetyl disulfide (PADS) which has an optimal combination of properties. This is best achieved by an initial ‘ageing’ of PADS for 48 hrs in acetonitrile with 3-picoline to generate polysulfides. The initial base-catalysed degradation of PADS occurs by an E1cB-type elimination to generate a ketene and acyldisulfide anion. Proton abstraction to reversibly generate a carbanion is demonstrated by H/D exchange, the rate of which is greatly increased by electron-withdrawing substituents in the aromatic ring of PADS. The ketene can be trapped intramolecularly by an o-allyl group. The disulfide anion generated subsequently attacks unreacted PADS on sulfur to give polysulfides, the active sulfurising agent. The rate of degradation of PADS is decreased by less basic substituted pyridines and is only first order in PADS indicating that the rate-limiting step is formation of the disulfide anion from the carbanion

Non-steroidal anti-inflammatory drugs (NSAIDs) in cancer pain:A database analysis to determine recruitment feasibility for a clinical trial

BACKGROUND: Insufficient evidence exists to support or refute use of NSAIDs for managing cancer pain. Palliative physicians support a placebo-controlled trial of NSAIDs as strong opioid adjuncts for cancer-induced bone pain as the most pragmatic design to benefit clinical practice. AIM: We aimed to determine patient numbers receiving palliative radiotherapy for cancer-induced bone pain, estimate the suitability of NSAID prescription and determine survival, guiding future trial feasibility. DESIGN: A retrospective observational database analysis was undertaken using 5 years of routinely collected regional radiotherapy and healthcare data, filtered to achieve a cohort with cancer-induced bone pain. Demographics and survival were linked to available serology and co-morbidity data. SETTING/PARTICIPANTS: Data was sourced from the regional Leeds Cancer Centre, a tertiary care setting. Patients who underwent palliative single fraction 8 gray (Gy) radiotherapy treatment for cancer-induced bone pain were included, totalling 2411 over 5 years. RESULTS: A mean of 478 patients received palliative radiotherapy for cancer-induced bone pain annually. Median age (IQR) was 70 (62–77); negatively skewed (−0.69). 65.3% died within 1 year of radiotherapy; 48.0% within 6 months. Age was not associated with survival on univariable analysis (HR 0.999 (95% CI 0.996–1.003)). Serology from 1063 patients (44.2%) were available; eGFR was ⩾60 mL/min/1.73 m(2) in 83.0%. From available data (1352 pts; 51.6% of sample), 20.2% had a coded co-morbidity contra-indicating NSAIDs. Combining serology and co-morbidities, 68.5% could be considered for NSAID prescription. CONCLUSIONS: Patient numbers at a regional radiotherapy centre support the feasibility of trial recruitment. Available serology and co-morbidity data suggest two-thirds may be suitable for NSAID prescription

Decay of heavy-light hybrids in HQET sum rules

The decay widths of the 0^{++} and 1^{-+} heavy-light hybrids to B(D) and pion are calculated by using the QCD sum rules. The interpolated current of the hybrid is chosen as $g\bar q\gamma_{\alpha}G_{\alpha\mu}^aT^ah_{\it v}(x)$. In order to simplify the calculation and avoid the ambiguity of three-point correlation function, a two-point correlation function between the pion and vacuum is used instead. The decay width of the $0^{++}\to B(D)$ is about 12(16) MeV while the $1^{-+}\to B(D)$ is around 0.4(1.8) MeV. We keep the leading order of 1/M_Q expansion in our calculation for convenience.Comment: 14 pages, latex file, 4 ps figs, Published version, some numerical results change

The 2011 Outburst of Recurrent Nova T Pyx: X-ray Observations Expose the White Dwarf Mass and Ejection Dynamics

The recurrent nova T Pyx underwent its sixth historical outburst in 2011, and became the subject of an intensive multi-wavelength observational campaign. We analyze data from the Swift and Suzaku satellites to produce a detailed X-ray light curve augmented by epochs of spectral information. X-ray observations yield mostly non-detections in the first four months of outburst, but both a super-soft and hard X-ray component rise rapidly after Day 115. The super-soft X-ray component, attributable to the photosphere of the nuclear-burning white dwarf, is relatively cool (~45 eV) and implies that the white dwarf in T Pyx is significantly below the Chandrasekhar mass (~1 M_sun). The late turn-on time of the super-soft component yields a large nova ejecta mass (>~10^-5 M_sun), consistent with estimates at other wavelengths. The hard X-ray component is well fit by a ~1 keV thermal plasma, and is attributed to shocks internal to the 2011 nova ejecta. The presence of a strong oxygen line in this thermal plasma on Day 194 requires a significantly super-solar abundance of oxygen and implies that the ejecta are polluted by white dwarf material. The X-ray light curve can be explained by a dual-phase ejection, with a significant delay between the first and second ejection phases, and the second ejection finally released two months after outburst. A delayed ejection is consistent with optical and radio observations of T Pyx, but the physical mechanism producing such a delay remains a mystery.Comment: Re-submitted to ApJ after revision

Gamma-ray bursts: Restarting the Engine

Recent gamma-ray burst observations have revealed late-time, highly energetic events which deviate from the simplest expectations of the standard fireball picture. Instead they may indicate that the central engine is active or restarted at late times. We suggest that fragmentation and subsequent accretion during the collapse of a rapidly rotating stellar core offers a natural mechanism for this.Comment: 8 pages, 1 figure; accepted by ApJ Letter